Voltage-gated sodium channels (VGSCs) set the threshold for action potential generation and conduct the electrical impulse down the neuronal axon. Functional changes to VGSCs affect the amplitude, threshold, and shape of the action potential and, consequentially, the extent and duration of neurotransmitter release. Early physiological studies indicated that VGSCs were not subject to regulation through second messenger pathways. We have determined that VGSCs are inhibited by a positive allosteric modulator of the calcium- sensing receptor (CaSR), a G-protein-coupled receptor expressed throughout the cerebral cortex. Surprisingly, this response is independent of the CaSR and abolished in the presence of GTP inhibitory analog GDP?S. These preliminary data indicate that the allosteric modulator, cinacalcet, activates a GTP-dependent protein pathway that modulates VGSC output, contradictory to the previously established ideas on VGSC regulation. The first aim of this proposal is to determine the mechanism of action of cinacalcet by delineating the pathway from its sit of action to modulation of VGSCs. We hypothesize that endogenous feedback inhibition of VGSCs may represent a novel form of synaptic plasticity, and such a pathway may be a therapeutic avenue for the amelioration of neurological diseases resulting from disruptions in VGSC behavior. VGSCs have different roles in action potential propagation dependent on terminal type. Due to the small size of nerve terminals at central synapses, direct methods have not yet been used to show how VGSCs at these sites affect the waveform of the action potential. Knowledge regarding VGSC function at these sites has been derived from recordings at large nerve terminals such as the calyx of Held or inferred from the action of ion channels at the soma, which may not accurately reflect events occurring at the terminal. The second aim will quantify the VGSC characteristics that contribute to the active properties of the small nerve terminals of central synapses and describe their function as it relates to synaptic transmission. This will be accomplished using a modified patch clamp technique developed in the Smith lab that allows for whole-bouton recordings to be made directly from small nerve terminals. Characterization of the nerve terminal will include determining VGSC density at the bouton and describing VGSC activation, inactivation, recovery from inactivation, and persistent current properties. Lastly, VGSC density at the nerve terminal will be experimentally manipulated to develop a computational model of how VGSCs at the terminal influence the action potential and postsynaptic neuronal response. Together, these aims will elucidate the role of VGSCs at small nerve terminals as well as potential mechanisms for their regulation at the synapse.